In recent years biodegradable polymeric nanoparticles have been proposed as new drug administration systems. One of the most important features that they offer is the controlled release of the incorporated drug. This leads to greater therapeutic efficacy, provides a more comfortable administration for the patient and allows preventing overdose. Furthermore, drugs with different physicochemical features can be included, enabling improving their stability in biological fluids. This fact is very important in the case of antigens, proteins and macromolecules in general. Furthermore due to their small size, nanoparticles are suitable for the administration of drugs through various routes, such as orally, parenterally and ocularly (Kreuter, Adv. Drug Del. Rev., 7 (1991) 71-86; Gref et al., Science, 263 (1994) 1600-1603; Zimmer and Kreuter, Adv. Drug Del. Rev., 16 (1995) 61-73).
Oral administration is the most convenient and popular route for the administration of drugs. However, the bioavailability of a certain active molecule depends (i) on the characteristics of the molecule of the drug and on the pharmaceutical form and (ii) on the physiological conditions present in the gastrointestinal tract, such as the presence of proteolytic enzymes, peristaltic movements and presystemic metabolism. Colloidal systems such as nanoparticles have been proposed to overcome some of these obstacles. These carriers essentially have a large specific surface whereby their interaction with the biological support (gastrointestinal mucosa) is facilitated. The drug release control also allows prolonging over time the effect of molecules with low biological half-lives. On the other hand, nanoparticles can be uptaken by Peyer's patch cells and by lymphoid tissue follicles (Hodges et al., J. Drug Target., 3 (1995) 57-60; Florence, Pharm. Res., 14 (1997) 259-266). This phenomenon allows directing the drug towards the lymphatic pathway, and in the case of vaccines facilitating their antigen presentation. However, conventional nanoparticles have several significant drawbacks with respect to their use by oral administration: (i) certain instability in gastrointestinal fluids, (ii) a low degree of intestinal absorption, and (iii) non-specific tropism or adhesion in the gastrointestinal mucosa.
Parenteral administration of nanoparticles provides controlled systemic release that is suitable for drugs with (i) low oral bioavailability, (ii) short biological plasma half-life and (iii) limited stability. Another significant advantage of parenteral nanoparticles is the possibility of concentrating the drug in a certain organ. However, nanoparticles are quickly recognized, uptaken and eliminated from the blood circulation by macrophages of the mononuclear phagocyte system (MPS) after their intravenous administration. This phenomenon limits their function in controlled release as well as the possibility of concentrating the drug in tissues other then MPS.
Ophthalmic administration of controlled release systems has significant advantages for the treatment of ocular diseases, although a systemic effect may also be obtained. However, ocular administration is associated to the quick elimination of the formulation from the precorneal area due to draining towards the nasolacrimal duct and lacrimal dilution. These processes give rise to the fact that a very low percentage of the administered drug may penetrate the cornea and reach intraocular tissues (less than 5%). This draining is responsible for the occurrence of systemic effects upon administering the formulation through this route. A number of studies have demonstrated that the use of nanoparticles allows increasing the amount of the drug in the conjunctiva and increasing their bioavailability compared with conventional ophthalmic forms such as solutions and ointments (Gurny et al., J. Controlled Rel., 6 (1987) 367-373; Deshpande et al., Crit. Rev. Ther. Drug Carrier Syst., 15 (1998) 381-420). Colloidal systems can be administered as simple drops avoiding vision problems due to their low viscosity. The frequency of use may be reduced due to the sustained release of the drug from the matrix of the nanoparticles. However, nanoparticles also show a quick elimination from the absorption site.
Therefore, even though nanoparticles are potentially useful for the various previously mentioned administration methods, there are still problems which make their use difficult. Modification of the characteristics of the polymeric matrix as well as of their surface may provide the solution to some of the problems described above.
From this point of view, the association or coating of nanoparticles with suitable polymers may modify their physicochemical characteristics, and it may indirectly modify their distribution and interaction with the biological medium. A possible strategy is polyethylene glycol (PEG) binding to the nanoparticles, known as pegylation or obtaining stealthy nanoparticles.
With respect to their use by oral administration, the association of polyethylene glycols to conventional nanoparticles allows protecting them against enzymatic attack in digestive fluids. This is because of the potential of polyethylene glycols to reject proteins (Gref et al., Science, 263 (1994) 1600-1603). This strategy would also allow minimizing their interaction with mucin and other proteins present in the lumen. A similar strategy has been applied to the development of the nanoparticles for ocular use. Fresta et al. observed a significant increase of the ocular absorption of acyclovir after its administration in poly(alkylcyanoacrylate) nanospheres coated with polyethylene glycol (Fresta et al., J. Pharm. Sci., 90 (2001) 288-297). This phenomenon is explained by a greater interaction of the coated nanoparticles with the corneal epithelium.
Various nanoparticles coated with polyethylene glycol administered intravenously have demonstrated prolonged circulation (Gref et al., Science, 263 (1994) 1600-1603; Stolnik et al., Pharm. Res., 11 (1994) 1800-1808; Bazile et al., J. Pharm. Sci., 84 (1995) 493-498). Poly(lactic) (PLA) nanoparticles coated with polyethylene glycol have a much longer plasma half-life (t½=6 h) than when they are coated with albumin or poloxamer (t½=2-3 minutes) (Verrecchia et al., J. Controlled Rel., 36 (1995) 49-61). The presence of hydrophilic polyethylene glycol chains on the surface of the nanoparticles significantly reduces their interaction with blood proteins (known as opsonins). These proteins promote phagocytosis forming a “bridge” between the particles and phagocytes (Frank & Fries, Immunol. Today, 12 (1991) 322-326). However, the hydrophilic properties of polyethylene glycols are not the only important factor providing efficient resistance to opsonization. Other hydrophilic polymers such as polyvinyl alcohol have demonstrated a low protecting ability against opsonization of the nanoparticles (Leroux et al., Life Sci., 57 (1995) 695-703). Therefore, the steric stabilization provided by pegylation would also be due to other physicochemical properties, such as the high flexibility of the PEG chains and a specific structural formation (Mosquiera et al., Biomaterials, 22 (2001) 2967-2979).
The main drawback with this new strategy is the stability of the association of polyethylene glycols to the surface of the nanoparticles (Peracchia et al., Life Sci., 61 (1997) 749-761). It is known that the ability of polyethylene glycol to reject proteins depends on the configuration, the charge, the length and the flexibility of the chains (Torchillin, J. Microencaps., 15 (1998) 1-19). The process for modifying the surface of the nanoparticles is mainly carried out by physical adsorption (Stolnik et al., Adv. Drug Del. Rev., 16 (1995) 195-214) or by covalent bonding (De Jaeghere et al., J. Drug Target., 8 (2000) 143-153). However, the drawback of simple adsorption is the quick loss of the coating due to the instability of the interaction. Given that covalent binding is preferable, most pegylated nanoparticles have been prepared using polyethylene glycol copolymers with lactic or glycolic acid. However, the copolymerization process requires the use of several catalysts and specific chemical conditions (Beletsi et al., Int. J. Pharm., 182 (1999) 187-197). Furthermore, the toxic organic solvent residues used in the organic synthesis (methylene chloride, toluene etc.), may be problematic.
Therefore, it is still necessary to obtain nanoparticles which are stable in oral administration, which maintain the hydrophilic coating and which have good bioadhesive characteristics and specificity in the gastrointestinal tract. They must be non-toxic, biodegradable and easy to produce in order to be effective.